Osteoclasts, the principal bone-resorbing cells, play a pivotal role in skeleton development and maintenance. Osteoclasts are derived from mononuclear precursors of monocyte/macrophage lineage upon stimulation of two key factors: monocyte/macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B (RANKL, also known as OPGL/ODF/TRANCE). RANKL, a member of the tumor necrosis factor (TNF) superfamily, regulates both osteoclast formation and function by binding to its receptor RANK expressed on osteoclast precursors and mature osteoclasts. The essential role of RANKL and RANK in the osteoclastogenic process has been demonstrated by the findings that mice lacking the gene for either protein develop osteopetrosis due to failure to form osteoclasts.
RANK (receptor activator of NF-κB) was identified as a member of the TNF receptor family. Members of the TNF receptor family lack intrinsic enzymatic activity. They usually transduce intracellular signals by recruiting various adaptor proteins such as TNF receptor associated factors (TRAFs) through specific motifs in the cytoplasmic domains. Since the unraveling of the RANKL/RANK system, efforts have been undertaken to elucidate RANK-initiated intracellular signaling. Many of these efforts have focused on the characterization of the receptor-proximal signaling events, which represent the initial components of RANK-mediated signaling. Although these studies have mapped RANK cytoplasmic regions by using in vitro binding assays, their physiological relevance to osteoclast biology remains largely unexplored.
The discovery of the RANKL/RANK/OPG regulatory axis has also raised high expectation for osteoprotegerin (OPG) and soluble RANK-Fc as therapeutic drugs for treating bone diseases. However, both OPG and RANK-Fc lack specificity, and the use of OPG or RANK-Fc may produce adverse effects on other biological processes that involve RANK, such as the development of immune system and mammary gland. Accordingly, there is a need for more specific RANK modulators and methods for identifying them.